The concept of atopic disease was introduced to describe an inherited generalized sensitivity to many different allergens. Although significant families aggregation for human allergy has been widely reported, the genetic basis for the resemblance has neither been well established nor characterized. Furthermore, the notion of a generalized sensitivity has recently been criticized and suggestions made that each specific allergy may have a unique component of transmission. In the present application we propose to address these issues about the inheritance of human allergy by focusing upon the transmission of IgE and its relationship to the expression and familial transmission of human allergy. Specifically, we seek to determine; a) whether a major gene influences IgE levels, b) if so whether this major gene contributes or explains familial resemblance for allergy and c) whether alternative allergies (e.g., asthma, eczema, etc.) are consistent in their genetic relationship to IgE, providing support for generalized inheritance, or inconsistent, providing support for some specific form of inheritance. The major analytic tool we will use to address these issues is segregation analysis applied to existing family data on IgE and allergy. Should major gene effects be found, then informative families will be indentified and the feasibility of linkage and biochemical studies investigated. We also propose to investigate the nature of family resemblance for serum immunoglobulin levels; IgA, IgD, IgE, IgG, and IgM; to identify major gene effects and to investigate the source of phenotypic associations among the immunoglobulins. For the latter, we propose to develop path analytic methods to study the joint transmission of two phenotypes in nuclear families. These methods will not only be applied to immunoglobulin levels, but also should be widely applicable for many studies for which the nuclear family is a popular sampling unit.